1. Field
The invention relates to N-(4-carbamimidoyl-phenyl)-glycine derivatives and methods for preparing and using such derivatives for treating diseases such as thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis, which are associated with coagulation factorsXa, IXa and thrombin.
2. Description
There is a continuing effort to identify compounds that inhibit the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIa and tissue factor. The subject invention provides new compounds that are useful and have activity for this purpose.
The subject invention provides a compound of the formula: 
wherein
R1 is hydrogen or the residue of an ester group that is cleavable under physiological conditions;
E is hydrogen or hydroxy;
three of the symbols X1 to X4, independent of each another, are each a group C(Ra), C(Rb) or C(Rc) and the fourth symbol is a group C(Rd) or N;
Ra to Rd, independent of each other, are each hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkynyloxy, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxyalkyl(alkyl)aminoalkyl, alkoxyalkylcarboxamido, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxycarbonylalkylcarboxamido, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkoxycarbonylcarboxamido, alkyl, alkyl(alkylcarbonyl)amino, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamido, alkylcarboxamidoalkoxy, alkylsulphanyl, alkylsulphanylalkoxy, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, alkylsulphonylaminoalkoxy, alkylureidyl, alkylthioureidyl, amino, aminoalkoxy, aryl, arylalkenyl, arylalkynyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylalkylcarboxamido, arylcarbonylalkoxy, arylcarboxamido, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, arylsulphonylamino, arylsulphonylaminoalkoxy, carboxy, carboxyalkyl, carboxyalkylcarboxamido, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carboxycarboxamido, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, cycloalkylcarboxamido, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, hydroxycycloalkylamino, mono- or di-alkylamino, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy, 2,2,2-trifluoroacetylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of azepanylcarbonylalkoxy, benzoimidazolyl, morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinylamino, piperidinylaminoalkyl, piperidinyloxy, alkylsulphonylpiperidinyloxy, furanylalkoxy, 1,3-dioxo-1,3-dihydroisoindolylalkyl, imidazolyl, imidazolylalkyl, isothiazolyloxy, dihydroisoxazolyl, piperazinyl, piperazinylalkyl, pyridinylaminoalkyl, bis-pyridinylalkylamino, pyridinyloxy, pyrimidinylaminoalkylazepanylideneamino, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxopyrrolidinylalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranylamino, tetrahydrothiopyranylamino, tetrahydropyranyloxy, dioxohexahydrothiopyranylamino, thiazolylalkoxy and thiophenyl, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, carboxyalkyl, hydroxy, tetrazolylmethoxy, alkylsulphonyl and alkoxycarbonylalkyl; or two adjacent groups Ra to Rd together form the remainder of a fused 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring,
provided that not more than three of Ra to Rd are the same and X1 is not substituted by carboxy or alkoxycarbonyl; and
one of the symbols G1 and G2 is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COOxe2x80x94Re or OCOxe2x80x94Re, where Re is alkyl or alkyl substituted by halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl, or arylcarbonyloxycarbonyl.
The subject invention also provides hydrates and solvates of the above compounds as well as physiologically usable salts of these compounds and their hydrates and solvates.
One preferred group of compounds are those where Ra to Rd, each independent of each other, are each hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamidoalkoxy, alkylsulphanylalkoxy, aminoalkoxy, aryl, arylalkenyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylcarbonylalkoxy, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, carboxy, carboxyalkyl, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinyloxy, pyridinylaminoalkyl, alkylsulphonylpiperidinyloxy, furanylalkoxy, imidazolylalkyl, isothiazolyloxy, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranyloxy and thiazolylalkoxy, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl and alkoxycarbonylalkyl, or two adjacent groups Ra to Rd together form the remainder of a 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring.
A further preferred group of compounds are those where Ra to Rd, each independent of each other, are each alkenyl, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylarylalkoxy, alkyl, alkylcarbonylalkoxy, alkylsulphanylalkoxy, arylcarboxamidoalkoxy, carbamoylalkoxy, carboxyarylalkoxy, cycloalkoxy, cycloalkylalkoxy, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of piperidinyloxy, furanylalkoxy, isothiazolyloxy, morpholinylalkyl, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy, tetrahydrofuranyloxy and tetrahydropyranyloxy, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl.
Another preferred group of compounds are those where Ra to Rd, each independent of each other, are each hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, cycloalkoxy, cycloalkylalkoxy, dihydroxyalkoxy, halogen, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy and tetrahydropyranyloxy, with the substituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl, and alkoxycarbonylalkyl.
Yet another preferred group of compounds are those where Ra to Rd, each independent of each other, are each hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, halogen, hydroxyalkoxy, hydroxycycloalkoxy or mono- or di-alkylaminoalkoxy or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl and tetrahydropyranyloxy, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl, and alkoxycarbonylalkyl.
Preferred groups for X are wherein X1 is the group C(Ra), X2 is the group C(Rb), X3 is the group C(Rc), and X4 is the group C(Rd). In such compounds, Ra is favorably hydrogen, carbamoylalkoxy, hydroxyalkoxy, or halogen, especially hydrogen; Rb is favorably hydrogen, alkenyl, alkynyl, alkoxy, or alkyl, especially alkoxy; Rc is favorably hydrogen, alkoxy, mono- or di-alkylaminoalkoxy, or hydroxyalkoxy, especially hydrogen or alkoxy; and Rd is favorably hydrogen, alkoxy, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl and tetrahydropyranyloxy, with the subtituent on the substituted heterocyclic substituent being alkyl or alkylsulphonyl.
It is also preferred that one of G1 and G2 is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl, or a group COOxe2x80x94Re or OCOxe2x80x94Re, where Re is alkyl or alkyl substituted with halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl, or arylcarbonyloxycarbonyl. More preferred combinations of G1 and G2 are hydrogen and hydroxy, especially hydrogen and hydrogen. R1 and E are favorably hydrogen.
The subject invention provides a preferred compounds of the formula: 
wherein,
Raxe2x80x2 is hydrogen, halogen, hydroxyalkoxy, or carbamoylalkoxy;
Rbxe2x80x2 is hydrogen, alkyl, alkoxy, hydroxycycloalkoxy, alkylpiperidinyloxy, alkylsulphonylpiperidinyloxy, tetrahydropyranyloxy, pyrrolidinylalkyl, alkenyl, or hydroxyalkoxy;
Rcxe2x80x2 is hydrogen, dialkylaminoalkoxy, hydroxyalkylalkoxy, hydroxyalkoxy, or alkoxy; and
Rdxe2x80x2 is hydrogen, dialkylaminoalkoxy, alkoxy, alkynyl, pyrrolidinylalkyl, pyridinylaminoalkyl, or morpholinylalkyl.
This preferred group of compounds also includes hydrates and solvates thereof, and physiologically usable salts of the above mentioned compounds.
Rather than reciting every combination of Raxe2x80x2, Rbxe2x80x2, Rcxe2x80x2, and Rdxe2x80x2, it is to be understood that all combinations of the recited substituents are possible to form compounds within the subject invention. For example, Raxe2x80x2 can be hydrogen, halogen, for example flourine, hydroxyalkoxy, hydroxyethoxy, carbamoylalkoxy, or carbamoylmethoxy in combination with any grouping of Rbxe2x80x2, Rcxe2x80x2, and Rdxe2x80x2.
One preferred combination is where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, for example (RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxyphenyl)-acetic acid or (RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid.
Another preferred combination is where Raxe2x80x2 is hydroxyalkoxy, Rbxe2x80x2 is hydrogen, Rcxe2x80x2 is alkoxy, and Rdxe2x80x2 is alkoxy, for example (RS)-(4-carbamimidoyl-phenylamino)-[4,5-diethoxy-2-(2-hydroxy-ethoxy)-phenyl]- acetic acid.
A further preferred combination is where Raxe2x80x2 is carbamoylmethoxy, Rbxe2x80x2 is hydrogen, Rcxe2x80x2 is alkoxy, and Rdxe2x80x2 is alkoxy, for example (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-4,5-diethoxy-phenyl)-acetic acid.
Preferred substituents for Rbxe2x80x2 include hydrogen, alkyl, alkoxy, hydroxycycloalkoxy, alkenyl, or hydroxyalkoxy, alkylpiperidinyloxy, alkylsulphonylpiperidinyloxy, or pyrrolidinylalkyl, and tetrahydropyranyloxy.
A preferred combination is where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkyl, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is dialkylaminoalkoxy, for example (RS)-(4-carbamimidoyl-phenylamino)-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-5-ethyl-phenyl]-acetic acid.
Yet another preferred combinaiton is where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is dialkylaminoalkoxy, and Rdxe2x80x2 is hydrogen, such as (RS)-(4-carbamimidoyl-phenylamino)-[4-(2-dimethylamino-ethoxy)-3-ethoxy-phenyl]-acetic acid.
Preferred combinations include: Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydroxyalkoxy, and Rdxe2x80x2 is hydrogen, for example (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methyl-ethoxy]-phenyl]-acetic acid; Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is alkoxy, and Rdxe2x80x2 is hydrogen, for example (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-4-methoxy-phenyl)-acetic acid hydrochloride; Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is pyridinylaminoalkyl, for example (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(pyridin-2-ylaminomethyl)-phenyl]-acetic acid; Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is morpholinylalkyl, for example (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-morpholin-4-yl-methyl-phenyl)-acetic acid; Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, for example (RS)-(4-carbamimidoyl-phenylamino)-3,5-diethoxy-phenyl)-acetic acid; and Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkoxy, Rcxe2x80x2 is hydroxyalkoxy, and Rd is hydrogen, for example (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid.
Another combination of Raxe2x80x2, Rbxe2x80x2, Rcxe2x80x2, and Rdxe2x80x2 that forms useful compounds within the subject invention is where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is hydroxycycloalkoxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, for example (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1-RS,2RS)-2-hydroxy-cyclopentyloxy]-phenyl]-acetic acid and (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxy-cyclohexyloxy]-phenyl]-acetic acid.
Also preferred is where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkenyl, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is pyrrolidinylalkyl, such as (RS)-(4-carbamimidoyl-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetic acid, and where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is hydroxyalkoxy, Rcxe2x80x2 is alkoxy, and Rdxe2x80x2 is alkoxy, such as (RS)-(4-carbamimidoyl-phenylamino)-[4,5-diethoxy-2-(3-hydroxypropoxy)-phenyl]-acetic acid.
Yet other preferred combinations are where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkylpiperidinyloxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, such as (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid; where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is alkylsulphonylpiperidinyloxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, such as (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(1-methane-sulphonyl-piperidin-4-yloxy)-phenyl]-acetic acid; and where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is pyrrolidinylalkyl, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkynyl, such as (RS)-(4-carbamimidoyl-phenylamino)-(3-ethynyl-5-pyrrolidin-1-ylmethyl-phenyl)-acetic acid.
Other of the subject compounds include combinations where Raxe2x80x2 is hydrogen, Rbxe2x80x2 is tetrahydropyranyloxy, Rcxe2x80x2 is hydrogen, and Rdxe2x80x2 is alkoxy, such as (4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)-phenyl]-acetic acid.
Of course as mentioned above, Rcxe2x80x2 can be individually hydrogen, dialkylaminoalkoxy, hydroxyalkylalkoxy, hydroxyalkoxy, or alkoxy, and Rdxe2x80x2 can be individually hydrogen, dialkylaminoalkoxy, alkoxy, alkynyl, pyrrolidinylalkyl, pyridinylaminoalkyl, or morpholinylalkyl. Each and every combination is to be considered as if written out explicitly.
The subject invention also provides for phamaceutical compositions containing the subject compounds, for example in galenical administration form. Also provided are methods for making and using the subject compounds.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention is concerned with novel N-(4-carbamimidoyl-phenyl)-glycine derivatives of the formula: 
wherein
R1 represents hydrogen or the residue of an ester group which is cleavable under physiological conditions;
E represents hydrogen or hydroxy;
three of the symbols X1 to X4 independently of one another represent a group C(Ra), C(Rb) or C(Rc) and the fourth represents a group C(Rd) or N;
Ra to Rd each independently represent hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkynyloxy, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxyalkyl(alkyl)aminoalkyl, alkoxyalkylcarboxamido, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxycarbonylalkylcarboxamido, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkoxycarbonylcarboxamido, alkyl, alkyl(alkylcarbonyl)amino, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamido, alkylcarboxamidoalkoxy, alkylsulphanyl, alkylsulphanylalkoxy, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, alkylsulphonylaminoalkoxy, alkylureidyl, alkylthioureidyl, amino, aminoalkoxy, aryl, arylalkenyl, arylalkynyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylalkylcarboxamido, arylcarbonylalkoxy, arylcarboxamido, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, arylsulphonylamino, arylsulphonylaminoalkoxy, carboxy, carboxyalkyl, carboxyalkylcarboxamido, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carboxycarboxamido, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, cycloalkylcarboxamido, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, hydroxycycloalkylamino, mono- or di-alkylamino, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy, 2,2,2-trifluoroacetylaminoalkoxy or a heterocyclic substituent selected from the group of azepanylcarbonylalkoxy, benzoimidazolyl, morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinylamino, piperidinylaminoalkyl, piperidinyloxy, alkylsulphonylpiperidinyloxy, furanylalkoxy, 1,3-dioxo-1,3-dihydroisoindolylalkyl, imidazolyl, imidazolylalkyl, isothiazolyloxy, dihydroisoxazolyl, piperazinyl, piperazinylalkyl, pyridinylaminoalkyl, bis-pyridinylalkylamino, pyridinyloxy, pyrimidinylaminoalkylazepanylideneamino, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxopyrrolidinylalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranylamino, tetrahydrothiopyranylamino, tetrahydropyranyloxy, dioxohexahydrothiopyranylamino, thiazolylalkoxy and thiophenyl, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, carboxyalkyl, hydroxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl or two adjacent groups Ra to Rd together forming the remainder of a fused 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring,
provided that not more than three of Ra to Rd have the same significance and X1 is not substituted by carboxy or alkoxycarbonyl; and
one of the symbols G1 and G2 represents hydrogen and the other represents hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COOxe2x80x94Re or OCOxe2x80x94Re and Re represents alkyl optionally substituted by halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl or arylcarbonyloxycarbonyl,
as well as hydrates or solvates and physiologically usable salts thereof.
Further, the invention is concerned with a process for the manufacture of the above compounds, pharmaceutical preparations that contain such compounds as well as the use of these compounds for the production of pharmaceutical preparations.
Examples of physiologically usable salts of these compounds of formula I are salts with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
The compounds of formula I can be solvated, especially hydrated. The hydration can take place in the course of the manufacturing process or can occur gradually as a consequence of hygroscopic properties of an initially anhydrous compound of formula I.
The compounds of formula I contain at least one asymmetric C atom and can therefore exist as an enantiomeric mixture, diastereomeric mixture or as optically pure compounds.
In the scope of the present invention xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, such as in alkoxy, alkoxycarbonyl etc., denotes a straight-chain or branched hydrocarbon residue containing 1-6, preferably 1-4 carbon atoms, such as, methyl, ethyl, propyl, isopropyl and butyl.
The term xe2x80x9calkoxyxe2x80x9d stands for the group alkyl-O- with alkyl as defined above, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy.
The term xe2x80x9calkenylxe2x80x9d stands for alone or in combination with other groups, a straight-chain or branched hydrocarbon residue containing an olefinic bond and up to 6, preferably up to 4 C-atoms.
The term xe2x80x9calkynylxe2x80x9d stands for alone or in combination with other groups, a straight-chain or branched hydrocarbon residue containing a triple bond and up to 6, preferably up to 4 C-atoms.
The term xe2x80x9ccycloalkylxe2x80x9d stands for a cyclic alkyl group of three to six carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9ccycloalkoxyxe2x80x9d or xe2x80x9ccycloalkyloxyxe2x80x9d denotes a cycloalkyl group that is bonded via an oxy (xe2x80x94Oxe2x80x94) group, such as e.g. cyclopentyloxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, such as in aryloxy, aralkyl etc. denotes a carbocyclic, aromatic residue such as phenyl, naphthyl or indanyl, preferably phenyl and naphthyl, especially phenyl, which can be substituted, e.g. by halogen, such as bromine, fluorine or chlorine, alkoxy, such as methoxy, ethoxy or propoxy, alkylenedioxy, such as methylenedioxy, hydroxy, nitro, amino, mono- or di-alkyl-amino, phenyl, phenoxy, COOH or COO-alkyl, such as COOCH3 or COOC2H5. Preferred substituents are alkoxy, halogen, preferably fluorine, alkyl, amino, nitro, dialkylamino and carboxy and especially alkoxy, halogen and alkyl. Examples of aralkyl groups are benzyl, phenethyl, mono- or dimethoxybenzyl, aminobenzyl or nitrobenzyl, examples of aryloxy groups are phenoxy or methoxycarbonyl-phenoxy and examples of aralkyloxy groups are benzyloxy, methoxybenzyloxy and phenethoxy.
The term xe2x80x9chalogenxe2x80x9d stands for fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
The term xe2x80x9chydroxyxe2x80x9d stands for the group xe2x80x94OH.
The term xe2x80x9ccarbonylxe2x80x9d stands for the group xe2x80x94C(O)xe2x80x94.
The term xe2x80x9ccarboxyxe2x80x9d stands for the group xe2x80x94C(O)OH.
The term xe2x80x9ccarboxamidoxe2x80x9d stands for the group stands for xe2x80x94C(O)xe2x80x94NHxe2x80x94.
The term xe2x80x9ccarbamoylxe2x80x9d stands for the group NH2xe2x80x94C(O)xe2x80x94.
The term xe2x80x9coxyxe2x80x9d stands for the group xe2x80x94Oxe2x80x94.
The term xe2x80x9caminoxe2x80x9d stands for the group xe2x80x94NH2.
The term xe2x80x9csulphanylxe2x80x9d stands for the group xe2x80x94Sxe2x80x94.
The term xe2x80x9csulphinylxe2x80x9d stands for the group xe2x80x94SOxe2x80x94.
The term xe2x80x9csulphonylxe2x80x9d stands for the group xe2x80x94SO2xe2x80x94.
The term xe2x80x9cureidylxe2x80x9d stands for the group NH2xe2x80x94C(O)xe2x80x94NHxe2x80x94.
The term xe2x80x9cthioureidylxe2x80x9d stands for the group NH2xe2x80x94C(S)xe2x80x94NHxe2x80x94.
Examples of haloalkyl are trifluoromethyl and pentafluoroethyl; examples of haloalkoxy are trifluoromethoxy and pentafluoroethoxy.
Examples of ester groups cleavable under physiological conditions denoted by R1 are alkyl, especially methyl and ethyl; morpholinoethyl; tetrahydropyranyl; alkoxycarbonyl-alkyl, such as tert.-butoxycarbonylmethyl (pivoxyl); alkoxycarbonyloxyalkyl, such as 1-(ethoxycarbonyloxy)ethyl, hexyloxycarbonyloxyalkyl (hexetil) and 1-isopropyloxycarbonyloxy)ethyl (proxetil); alkylcarbonyloxyalkyl, such as 1-acetoxyethyl (axetil), 1-(pivaloyloxy)ethyl and 1-(cyclohexylacetoxy)ethyl. Especially preferred ester groups are methyl and ethyl, particularly ethyl.
The invention includes especially the aforementioned compounds in which three of the symbols X1 to X4 independently of one another represent a group C(Ra), C(Rb) or C(Rc) and the fourth represents a group C(Rd).
In a preferred embodiment the present invention embraces especially compounds as defined above in which Ra to Rd independently of one another represent hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamidoalkoxy, alkylsulphanylalkoxy, aminoalkoxy, aryl, arylalkenyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylcarbonylalkoxy, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, carboxy, carboxyalkyl, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy or a heterocyclic substituent selected from the group of morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinyloxy, pyridinylaminoalkyl, alkylsulphonylpiperidinyloxy, furanylalkoxy, imidazolylalkyl, isothiazolyloxy, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranyloxy and thiazolylalkoxy, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl or two adjacent groups Ra to Rd together forming the remainder of a fused 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring.
Especially preferred are the compounds defined above in which Ra to Rd independently of one another represent hydrogen, alkenyl, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylarylalkoxy, alkyl, alkylcarbonylalkoxy, alkylsulphanylalkoxy, arylcarboxamidoalkoxy, carbamoylalkoxy, carbonylarylalkoxy, cycloalkoxy, cycloalkylalkoxy, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy or heterocyclic substituent selected from the group of piperidinyloxy, furanylalkoxy, isothiazolyloxy, morpholinylalkyl, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy, tetrahydrofuranyloxy and tetrahydropyranyloxy, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl.
Further preferred compounds are those in which Ra to Rd independently of one another represent hydrogen, alkenyl, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkoxy, alkylsulphanylalkoxy, arylcarboxamidoalkoxy, alkoxycarbonylarylalkoxy, carbamoylalkoxy, carboxyarylalkoxy, cycloalkoxy, cycloalkylalkoxy, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy or heterocyclic substituent selected from the group of piperidinyloxy, furanylalkoxy, isothiazolyloxy, morpholinylalkyl, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy, tetrahydrofuranyloxy and tetrahydropyranyloxy, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl.
Particularly preferred compounds are those in which Ra to Rd independently of one another represent hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, cycloalkoxy, cycloalkylalkoxy, dihydroxyalkoxy, halogen, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy or heterocyclic substituent selected from the group of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy and tetrahydropyranyloxy, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl.
In a further preferred embodiment of the invention compounds are preferred in which Ra to Rd independently of one another represent hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, halogen, hydroxyalkoxy, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy or heterocyclic substituent selected from the group of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl and tetrahydropyranyloxy, with the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl or alkoxycarbonylalkyl.
In a particular embodiment the invention relates to the aforementioned compounds in which X1 represents the group C(Ra), X2 represents the group C(Rb), X3 represents the group C(Rc) and X4 represents the group C(Rd).
The invention embraces especially compounds in accordance with the above definitions in which Ra represents hydrogen, carbamoylalkoxy, hydroxyalkoxy or halogen, preferably hydrogen.
Furthermore, the invention also relates in particular to compounds in accordance with the above definitions in which Rb represents hydrogen, alkenyl, alkynyl, alkoxy or alkyl, preferably alkoxy.
Moreover, the invention relates especially to compounds as defined above in which Rc represents hydrogen, alkoxy, mono- or di-alkylaminoalkoxy or hydroxyalkoxy, particularly hydrogen or alkoxy.
In a further particular embodiment the invention embraces compounds in accordance with the above definitions in which Rd represents hydrogen, alkoxy, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy or a heterocyclic substituent selected from the group of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl or tetrahydropyranyloxy, with the heterocyclic substituents being optionally substituted with alkyl or alkylsulphonyl.
Furthermore, the invention embraces especially compounds in accordance with the above definitions in which one of the symbols G1 and G2 represents hydrogen and the other represents hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COOxe2x80x94Re or OCOxe2x80x94Re and Re represents alkyl optionally substituted with halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl or arylcarbonyloxycarbonyl.
Preferred compounds in accordance with the above definitions are those in which one of the symbols G1 and G2 represents hydrogen or hydroxy and the other represents hydrogen. In a particular embodiment both symbols G1 and G2 represent hydrogen.
Furthermore, compounds in accordance with the above definitions in which R1 represents hydrogen are preferred.
Preferred compounds in accordance with the above definitions are also those in which the symbol E represents hydrogen.
In a particular embodiment of the compounds described above there are preferred those in which not more than two of Ra to Rd are simultaneously hydrogen.
In a further embodiment the invention relates to the compounds described above in which X1 represents the group C(Ra) and X2, X3 and X4 independently of one another represent a group selected from the groups C(Rd), C(Rb) and C(Rc). Moreover, the invention relates to the compounds defined above in which X2 represents the group C(Rb) and X1, X3 and X4 independently of one another represent a group selected from the groups C(Rd), C(Ra) and C(Rc). The invention furthermore relates to the compounds described above in which X3 represents the group C(Rc) and X1, X2 and X4 independently of one another represent a group selected from the groups C(Rd), C(Rb) and C(Ra). Moreover, the invention relates to the compounds described above in which X4 represents the group C(Rd) and X1, X2 and X3 independently of one another represent a group selected from the groups C(Ra), C(Rb) and c(Rc).
In particular, preferred compounds are the compounds of formula I described in the Examples as individual compounds in the form of the free acids, their esters as well as hydrates or solvates and physiologically usable salts thereof.
Preferred individual compounds are those selected from the group consisting of:
a) (RS)-(4-carbamimidoyl-phenylamino)-[4-(2-dimethylamino-ethoxy)-3-ethoxy-phenyl]-acetic acid;
b) (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1-RS,2RS)-2-hydroxy-cyclopentyloxy]-phenyl]-acetic acid;
c) (RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid;
d) (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid;
e) (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methyl-ethoxy]-phenyl]-acetic acid;
f) (RS)- and (SR)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxy-cyclohexyloxy]-phenyl]-acetic acid;
g) (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(1-methanesulphonylpiperidin-4-yloxy)-phenyl]-acetic acid;
h) (4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)-phenyl]-acetic acid;
i) (RS)-(4-carbamimidoyl-phenylamino)-(3-ethynyl-5-pyrrolidin-1-ylmethylphenyl)-acetic acid;
j) (RS)-(4-carbamimidoyl-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinylphenyl)-acetic acid;
k) (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-4-methoxy-phenyl)-acetic acid hydrochloride;
l) (RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid;
m) (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(pyridin-2-ylaminomethyl)-phenyl]-acetic acid;
n) (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-morpholin-4-ylmethyl-phenyl)-acetic acid;
o) (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid;
p) (RS)-(4-carbamimidoyl-phenylamino)-[4,5-diethoxy-2-(2-hydroxy-ethoxy)-phenyl]-acetic acid;
q) (RS)-(4-carbamimidoyl-phenylamino)-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-5-ethyl-phenyl]-acetic acid;
r) (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid;
s) (RS)-(4-carbamimidoyl-phenylamino)-[4,5-diethoxy-2-(3-hydroxy-propoxy)-phenyl]-acetic acid; and
t) (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-4,5-diethoxy-phenyl)-acetic acid.
The compounds of formula I can be obtained by converting the nitrile group in a compound of formula: 
wherein X1, X2, X3, X4, R1 and E have the significance given above,
into a carbamimidoyl group or into a N-hydroxy-carbamimidoyl group and, if desired, modifying a reactive group present in an obtained compound of formula I and, if desired, converting a compound of formula I obtained into a physiologically compatible salt or converting a salt of a compound of formula I into the free acid or base.
The conversion of the nitrile group in a compound of formula II into a carbamimidoyl group xe2x80x94C(NH)NH2 or a N-hydroxy-carbamimidoyl group xe2x80x94C(NOH)NH2 can be carried out according to methods known per se. For example, the conversion into a N-hydroxy-carbamimidoyl group can be performed by dissolving a compound of formula II in a solvent, such as DMF, ethanol or methanol, treating the solution with hydroxylamine or a salt of hydroxylamine with an inorganic acid, such as hydroxylamine hydrochloride, and thereafter with a base, such as diisopropylethylamine or triethylamine, sodium hydride or sodium methanolate, conveniently at a temperature up to 80xc2x0 C.
The conversion of the nitrile group into a carbamimidoyl group can be carried out e.g. by treating a compound of formula II in a solvent, such as ethanol or methanol, or a solvent mixture, such as chloroform and methanol or chloroform and ethanol, with a dry stream of hydrogen chloride, conveniently at a temperature below 10xc2x0 C., thereafter treating the reaction solution with a solvent, such as diethyl ether, and filtering off the precipitated iminoether. The thus-obtained material is treated in a solvent, such as methanol or ethanol, either with gaseous ammonia or an ammonium salt, such as ammonium chloride, conveniently at a temperature up to 80xc2x0 C. Alternatively, the solution containing the iminoether can be evaporated and the residue can be treated with gaseous ammonia or an ammonium salt in methanol or ethanol. In an analogous manner, the iminoether can be converted into a N-hydroxy-carbamimidoyl compound of formula I with hydroxylamine or a salt thereof in the presence of a base.
As modifications of functional groups present in a compound of formula I there come into consideration especially the conversion of a N-hydroxy-carbamimidoyl group into a carbamimidoyl group, the esterification of a carboxy group, the saponification of an ester group and the cleavage of an ether group, such as an arylalkyl ether group, e.g. the benzyl ether group. All of these reactions can be carried out according to methods known per se.
For the conversion of a N-hydroxy-carbamimidoyl group into a carbamimidoyl group, an amidoxime of formula I can be hydrogenated in a solvent, such as ethanol, methanol, dioxan, THF or glacial acetic acid, or a solvent mixture, such as ethanol and glacial acetic acid, with hydrogen and a catalyst, such as palladium, platinum or nickel. In so doing, other reactive groups present in the compound of formula I and reactive towards the reducing agent can be modified. For example, in the case of hydrogenation with palladium a benzyloxy group Ra, Rb, Rc or Rd is converted into the hydroxy group.
By reacting a compound of formula I in which G1 and G2 represent hydrogen with a chloroformic acid ester of the formula ClC(O)Oxe2x80x94Re in which Re has the significance set forth above and wherein a hydroxy or carboxy group is present in protected form, in a solvent, such as dichloromethane, dioxan or DMF, or a solvent mixture, such as dichloromethane and water or ethyl acetate and water, in the presence of an organic base, such as pyridine or triethylamine, or an inorganic base, such as sodium hydroxide, sodium carbonate or potassium hydrogen carbonate, there is obtained the corresponding compound of formula I in which G1 and G2 represent the group xe2x80x94C(O)Oxe2x80x94Re. Analogously, a compound of formula I in which G1 and G2 represent hydrogen can be converted with a p-nitrophenyl carbonate of the formula p-NO2C6H4OCOOxe2x80x94Re into the corresponding compound of formula I in which one of G1 and G2 represents xe2x80x94COOxe2x80x94Re. The reaction is carried out by treating the p-nitrophenyl carbonate in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which G1 and G2 represent hydrogen.
By reacting a compound of formula I in which G1 and G2 represent hydrogen with an acyl chloride, such as an aroyl chloride, there is obtained the corresponding compound of formula I in which one of G1 and G2 represents hydrogen and the other represents acyl. The reaction is carried out by treating the acyl chloride in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which G1 and G2 represent hydrogen.
Compounds of formula I in which G1 or G2 represents a group xe2x80x94COOxe2x80x94Re and Re represents alkyl substituted by alkylcarbonyloxy or aroyloxy can be manufactured according to methods known per se (Synthesis 1990, p.1159-66; J.Med.Chem. 31, p.318-22, 1988) by reacting the carbamimidoyl compound with a p-nitrophenyl-alkanoyloxy-ethyl carbonate.
By reacting a compound of formula I in which one of the residues G1 and G2 represents hydroxy and the other represents hydrogen with an acyl halide there can be obtained a compound of formula I in which one of the residues G1 and G2 represents xe2x80x94OCORe. The reaction is carried out by treating the acyl chloride in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which G1 and G2 represent hydrogen.
The compounds of formula II can be prepared according to methods known per se, e.g. as described hereinafter and/or as described in the Examples or in analogy to these methods. For example, an aldehyde of formula: 
in which X1, X2, X3 and X4 have the significances given above, can be reacted with a p-aminobenzonitrile of formula: 
wherein E has the significance given above,
and benzyl isonitrile and a primary alkanol such as methanol or ethanol, in the prescence of boron trifluoride etherate. Hydrolysis of the resulting iminoether with water yields a compound of formula II in which R1 represents methyl or ethyl. By hydrolysis of the ester group R1, e.g. by treatment with LiOH in tetrahydrofuran, there is obtained a compound of formula II in which R1 represents hydrogen.
Further reactions for the preparaton f compounds of formula II:
By reaction of compounds of formula II in which one or more of Ra-Rd 
represents alkylthio with an oxidizing agent such as e.g. meta-chlorperbenzoic acid or ozone in a suitable solvent such as acetone-water or methylene chloride there is obtained a compound of formula II in which the alkylthio group is converted into an alkylsulphinyl or alkylsulphonyl group;
represents alkoxy such as methoxy, isopropoxy or benzyloxy with a Lewis acid such as boron tribromide or boron trichloride in a suitable solvent such as methylene chloride or optionally by catalytic hydrogenation in e.g. ethyl acetate or ethanol there are obtained compounds of formula II in which the alkoxy group is converted into a hydroxy group;
represents hydroxy
with an alkylating agent such as an alkyl bromide, alkyl iodide or alkyl mesylate in the presence of a base such as potassium carbonate or caesium carbonate in a solvent such as DMF or acetone or
by a Mitsunobu reaction with an alkohol in the presence of DEAD and triphenylphosphine in a solvent such as THF or Dioxan or
by reaction with an epoxide such as cyclopentene oxide in the presence of a base such as potassium carbonate, preferably at a temperature up to 150xc2x0 C. there are obtained compounds of formula II in which the hydroxy group is converted into an alkoxy group;
represents hydroxy with an aryl- or heteroarylboronic acid such as phenylboronic acid or 3-pyridylboronic acid in the presence of copper acetate and a base such as Pyridine or triethylamine in a solvent such as methylene chloride there are obtained compounds of formula II in which the hydroxy group is converted into an aryloxy or heteroaryloxy group;
represents hydroxy with trifluoromethanesulphonic anhydride in the presence of a base such as pyridine or triethylamine and in a suitable solvent such as methylene chloride or THF and subsequent reaction with an aryl- or heteroarylboronic acid such as pyridineboronic acid or thiopheneboronic acid in the presence of a suitable catalyst such as tetrakis-(triphenylphosphine)-palladium in a solvent such as toluene, preferably at a temperature up to 100xc2x0 C., there are obtained compounds of formula II in which the hydroxy group is converted into an aryl or heteroaryl group;
represents nitro by catalytic hydrogenation in the presence of e.g. a palladium-charcoal catalyst in a solvent such as ethanol or THF there are obtained compounds of formula II in which the nitro group is converted into an amino group;
represents amino with
an alkylating agent such as an alkyl halide or alkyl mesylate in the presence of a base such as Hxc3xcnig""s base or triethylamine in a solvent such as THF, preferably at an elevated temperature, or
a carbonyl compound such as pyridinecarboxaldehyde or 1-methyl-4-piperidone in the presence of a reducing agent, such as e.g. sodium triacetoxyborhydride in a solvent such as ethyl acetate, or
an epoxide such as e.g. cyclopentene oxide in the presence of a perchlorate salt such as lithium perchlorate in a solvent such as acetonitrile, preferably at an elevated temperature there are obtained compounds of formula II in which the amino group is converted into an alkylamino or dialkylamino group;
represents amino with an acid chloride such as cyclopentanecarboxylic acid chloride, phenylsulphonyl chloride or butylsulphamoyl chloride in the presence of a base such as triethylamine or Hxc3xcnig""s base and in an inert solvent such as THF or methylene chloride there are obtained compounds of formula II in which the amino group is converted into an amide or sulphonamide or sulphamide group;
represents amino with an isocyanate such as e.g. butyl isocyanate in a suitable solvent such as THF there are obtained compounds of formula II in which the amino group is converted into a urea group;
represents halogen
with an acetylene compound such as e.g. trimethylsilylacetylene in the presence of palladium acetate and triphenylphosphine in a solvent such as triethylamine
in a Stille reaction with a stannane such as e.g. allyltributylstannane or tributylethynylstannane in the presence of a catalyst such as tetrakis-(triphenylphosphine)-palladium and in a suitable solvent such as dimethylacetamide, preferably at an elevated temperature, there are obtained compounds of formula II in which the halogen substituent is converted into an in allyl or alkynyl or vinyl group;
represents halogen in a Suzuki reaction with an aryl- or heteroarylboronic acid such as phenylboronic acid or 3-pyridylboronic acid in the presence of tetrakis-(triphenylphosphine)-palladium and a base such as e.g. potassium carbonate and in a solvent such as toluene or dioxan there are obtained compounds of formula II in which the halogen substituent is converted into an aryl or heteroaryl group;
represents halogen with a boronic acid ester such as bis(pinacolato)diboron in the presence of potassium acetate and bis-(triphenylphosphine)-palladium-(II) chlorid in a solvent such as dioxan and subsequent reaction with aryl or heteroaryl halides such as e.g. 3-bromopyridine in the presence of potassium carbonate and tetrakis-(triphenylphosphine)-palladium in a solvent such as toluene at an elevated temperature there are obtained compounds of formula II in which the halogen substituent is converted into an aryl or heteroaryl group;
represents alkenyl or alkynyl by catalytic hydrogenationin the presence of e.g. palladium-charcoal as the catalyst and in a solvent such as ethanol, ethanol-acetic acid or THF there are obtained compounds of formula II in which the akenyl or alkynyl group is reduced to an alkyl group;
represents vinyl in a 3+2 cycloaddition with e.g. nitroethane and di-tert-butyl dicarbonate in the presence of dimethylaminopyridine in a solvent such as acetonitrile there are obtained compounds of formula II in which the vinyl group is converted into a dihydroisoxazole group;
represents hydroxymethyl with methanesulphonyl chloride in the presence of a base such as triethylamine and in a solvent such as methylene chloride or THF and subsequent reaction with a suitable amine such as e.g. pyrrolidine or morpholine in a solvent such as THF there are obtained compounds of formula II in which the hydroxymethyl group is converted into a mono- or di-alkylaminomethyl group;
represents hydroxymethyl with an oxidizing agent such as oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine and in a solvent such as methylene chloride, preferably at a low temperature, there are obtained compounds of formula II in which the hydroxymethyl group is converted into a formyl group;
represents formyl in a Wittig reaction with an alkyltriphenylphosphonium halide such as e.g. methyl-triphenylphosphonium bromide in the presence of a base such as e.g. potassium carbonate in a solvent such as dioxan-water, preferably at an elevated temperature there are obtained compounds of formula II in which the formyl group is converted into an alkenyl group;
represents formyl with an amine such as e.g. pyrrolidine and a suitable reducing agent such as sodium cyanoborhydride in a solvent such as methanol at einem pH von 6, adjusted with e.g. acetic acid, there are obtained compounds of formula II in which the formyl group is converted into an alkylaminomethyl group;
represents formyl
with a 1,2-diamine such as e.g. 1,2-phenylenediamine in the presence of an oxidizing agent such as DDQ in a solvent such as acetonitrile or
mit glyoxal and ammonia in water-ethanol there are obtained compounds of formula II in which the formyl group is converted into an imidazolyl group;
represents benzyloxycarbonyl-alkoxy by catalytic hydrogenation in the presence of e.g. palladium-charcoal as the catalyst in a solvent such as ethanol-acetic acid there are obtained compounds of formula II in which the benzyloxycarbonyl-alkoxy group is converted into a carboxy-alkoxy group;
represents carboxy-alkoxy with an amine such as e.g. pyrrolidine or morpholine and a coupling reagent such as e.g. BOP in the presence of a base such as 4-ethylmorpholine and in a solvent such as DMF there are obtained compounds of formula II in which the carboxy-alkoxy group is converted into a carbamoylalkoxy.
Compounds of formula III are known per se. They can be obtained e.g. by reacting compounds of formula III in which one or more of Ra-Rd 
is a hydroxy group
with an alkylating agent such as e.g. benzyl bromide or ethyl bromide in the presence of a base such as potassium carbonate oder caesium carbonate in a suitable solvent such as DMF or acetone, preferably at an elevated temperature, or
in a Mitsunobu reaction with an alcohol in the presence of DEAD and triphenylphosphine in a solvent such as THF or Dioxan to give compounds of formula II in which the hydroxy group is substituted by an alkoxy group;
is a formyl group in a Wittig reaction with an alkyltriphenylphosphonium halide such as e.g. methyl-triphenylphosphonium bromide in the presence of a base such as e.g. potassium carbonate in a solvent such as dioxan-water, preferably at an elevated emperature, to give compounds of formula II in which the formyl group is substituted by an alkenyl group.
Compounds of formula III in which one of the residues Ra-Rd represents alkylthio or 1-hydroxyalkyl can also be obtained by reacting an aldehyde, protected e.g. as an acetal or aminal, with the residue Ra-Rd in question being either hydrogen, bromine or iodine, with a strong base such as e.g. butyl-lithium in e.g. THF and subsequent reaction with disulphides such as e.g. dimethyl disulphide in a solvent such as THF or aldehydes such as e.g. acetaldehyde as well as subsequent deprotection of the aldehyde function with an aqueus acid.
Compounds of formula III can also be obtained by
formylation of a suitably substituted aromatic according to conventional methods such as Vilsmeier reaction, reaction with titanium tertrachloride and dichloromethyl methy lether, reaction with chloroform-sodium hydroxide or with hexamethylenetetramine and acetic acid;
oxidation of a benzyl alcohol according to known methods, e.g. by means of manganese dioxide;
reaction of a toluene derivative N-bromosuccinimide in the presence of a radical initiator, e.g. AIBN, and subsequent reaction with 2-nitropropane in the presence of a base such as sodium ethylate.
Insofar as their preparation is not described in the Examples, the compounds of formulas III and IV can be prepared according to the methods set forth above or according to analogous methods.
The compounds of formula I, their solvates and salts inhibit the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIa and tissue factor. These compounds consequently influence both platelet aggregation which is induced by these factors and plasmatic blood coagulation. They therefore inhibit the formation of thrombi and can be used for the control or prevention of diseases, such as thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis. Furthermore, these compounds have an effect on tumor cells and prevent metastases. They can therefore also be employed as antitumor agents.
Accordingly, the present invention also relates to a pharmaceutical preparation containing a compound as described above in a galenical administration form.
The invention likewise embraces compounds as described above for use as medicaments, especially as inhibitors of the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIa and tissue factor, particularly as medicaments for the treatment or prevention of thromboses, apoplexy, cardiac infarction, inflammation and arteriosclerosis or as antitmour agents.
Moreover, the invention relates to the use of a compound as described above for the production of medicaments containing a compound as described above for the treatment or prevention of thromboses, apoplexy, cardiac infarction, inflammation and arteriosclerosis or of antitmour agents.
The inhibition of the amidolytic activity of factor VIIa/tissue factor complex by the compounds in accordance with the invention can be demonstrated with the aid of a chromogenic peptide substrate as described hereinafter.
The measurements were carried out on microtitre plates at room temperature. To this end, 100 xcexcl of a solution of 26 nM of tissue factor, 9 nM of soluble factor VIIa and 8 mM of calcium chloride were added to 25 xcexcl of a solution of the inhibitor in a buffer [pH 7.5, 100 mM, comprising 0.14M NaCl, 0.1M N-(2-hydroxyethyl)piperazine-Nxe2x80x2-(2-ethanesulphonic acid) (HEPES), 0.5 mg/l of fatty-acid-free BSA (bovine serum albumin) and 0.05% NaN3] in each well of the plate. After an incubation time of 15 minutes the reaction was started by the addition of 50 xcexcl of chromogenic substrate Chromozym-tPA (3.5 mM, MeSO2-D-Phe-Gly-Arg-paranitroanilide) and the hydrolysis of the substrate was followed spectrophotometrically on a kinetic microtitre plate reader over 10 minutes. Using the plot of the inhibition curves, the Ki values were determined according to the method described in Biochem. J. 55, 1953, 170-171. The results will be evident from the following Table (Ki in xcexcM/l):
The activity of the low molecular weight substances can, moreover, be characterized in the xe2x80x9cprothrombin timexe2x80x9d (PT) clotting test. The substances are prepared as a 10 mM solution in DMSO or DMSO/0.1M HCl (DHCl) and thereafter made up to the desired dilution in the same solvent. Thereafter, 0.25 ml of human plasma (obtained from whole blood anticoagulated with {fraction (1/10)} volume of 108 mM Na citrate) was placed in the instrument-specific sample container. In each case 5 xcexcl of each dilution of the substance-dilution series was then mixed with the plasma provided. This plasma/inhibitor mixture was incubated at 37xc2x0 C. for 2 minutes. Thereafter, there were pipetted to the semi-automatic device (ACL, Automated Coagulation Laboratory (Instrument Laboratory)) 50 xcexcl of plasma/inhibitor mixture in the measurement container. The clotting reaction was initiated by the addition of 0.1 ml of Innovin(copyright) (recombinant human tissue factor combined with calcium buffer and synthetic phospholipids(Dade Behring(copyright), Inc.). The time up to the fibrin cross-linking was determined photooptically from the ACL. The inhibitor concentration, which brought about a doubling of the PT clotting time, was determined by means of a graph.
The Ki value of the compounds of the present invention preferably amounts to about 0.1 to 500 nM, especially about 0.1 to 100 nM. The PT values preferably amount to about 0.1 to 10 xcexcM, especially to about 0.1 to 5 xcexcM.
As mentioned earlier, medicaments containing a compound of formula I, a solvate or a salt thereof also form an object of the present invention, as does a process for the production of such medicaments which comprises bringing one or more of such compounds, solvates or salts and, if desired, other therapeutically useful substances into a galenical administration form. These medicaments can be administered orally, e.g. in the form of dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories, or as a spray. However, administration can also be carried out parenterally, e.g. in the form of injection solutions.
For the production of tablets, coated tablets, dragxc3xa9es and hard gelatine capsules, the active ingredient can be mixed with pharmaceutically inert, inorganic or organic excipients. Suitable excipients for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules are, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; depending on the nature of the active ingredient no excipients are, however, usually required in the case of soft gelatine capsules. Suitable excipients for the production of solutions and syrups are e.g. water, polyols, sucrose, invert sugar and glucose; suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol and vegetable oils, and suitable excipients for suppositories are natural and hardened oils, waxes, fats, semi-liquid or liquid polyols. In addition, the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.
The dosage of the active ingredient for the control or prevention of the illnesses mentioned above can vary within wide limits and will, of course, be adapted to the individual requirements in each particular case. In general, in the case of oral or parenteral, e.g. intravenous or subcutaneous, administration, a dose of about 0.1 to 20 mg/kg, preferably about 0.6 to 4 mg/kg, per day should be adequate for adults, although the upper limit which has just been mentioned may be exceeded or the dose may be lower when this is shown to be indicated.